WO1994010997A1 - Taxanes a chaine laterale a substitution alkyle et compositions pharmaceutiques les contenant - Google Patents

Taxanes a chaine laterale a substitution alkyle et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO1994010997A1
WO1994010997A1 PCT/US1993/010816 US9310816W WO9410997A1 WO 1994010997 A1 WO1994010997 A1 WO 1994010997A1 US 9310816 W US9310816 W US 9310816W WO 9410997 A1 WO9410997 A1 WO 9410997A1
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Prior art keywords
hydrogen
solution
hydroxy
alkyl
alkenyl
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PCT/US1993/010816
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English (en)
Inventor
Robert A. Holton
Ki-Byung Chai
Hamid Idmoumaz
Hossain Nadizadeh
Yukio Suzuki
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Florida State University
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Priority claimed from US07/976,331 external-priority patent/US5284865A/en
Priority claimed from US08/005,229 external-priority patent/US5338872A/en
Priority claimed from US08/010,798 external-priority patent/US5399726A/en
Priority claimed from US08/026,978 external-priority patent/US5990325A/en
Priority claimed from US08/034,247 external-priority patent/US5430160A/en
Priority to ES94901360T priority Critical patent/ES2199955T3/es
Application filed by Florida State University filed Critical Florida State University
Priority to JP51229994A priority patent/JP3933196B2/ja
Priority to AU55976/94A priority patent/AU689451B2/en
Priority to DE69332979T priority patent/DE69332979T2/de
Priority to CA002147854A priority patent/CA2147854C/fr
Priority to DK94901360T priority patent/DK0667772T3/da
Priority to AT94901360T priority patent/ATE240099T1/de
Priority to EP94901360A priority patent/EP0667772B9/fr
Publication of WO1994010997A1 publication Critical patent/WO1994010997A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/60—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members
    • C07C2603/62—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members containing three- or four-membered rings

Definitions

  • the present invention is directed to novel taxanes which have utility as antileukemia and antitumor agents.
  • Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibiting activity. Taxol has a 2'R, 3'S configuration and the following structural formula:
  • taxol is currently undergoing clinical trials in both France and the United States.
  • R' represents hydrogen or acetyl and one of R" and R''' represents hydroxy and the other represents tert-butoxycarbonylamino and their stereoisomeric forms, and mixtures thereof.
  • the compound of formula (2) in which R'' is hydroxy, R''' is tert-butoxycarbonylamino having the 2'R, 3'S configuration is commonly referred to as taxotere.
  • taxol and taxotere are promising chemotherapeutic agents, they are not universally effective. Accordingly, a need remains for additional chemotherapeutic agents.
  • the present invention is directed to taxane derivatives having a C13 side chain which includes an alkyl substituent.
  • the taxane derivative has a tricyclic or tetracyclic core and corresponds to the formula:
  • X 1 is -OX 6 , -SX 7 , or -NX 8 X 9 ;
  • X 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
  • X 3 is alkyl
  • X 4 is hydrogen
  • X 5 is -COX 10 , -COOX 10 , -COSX 10 , -CONX 8 X 10 , or -SO 2 X 11 ;
  • X 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative;
  • X 7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group
  • X 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
  • X 9 is an amino protecting group
  • X 10 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
  • X 11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OX 10 , or -NX 8 X 14 ;
  • X 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
  • R 1 is hydrogen, hydroxy, protected hydroxy or together with R 14 forms a carbonate
  • R 2 is hydrogen, hydroxy, -OCOR 31 together with R 2a forms an oxo
  • R 2a is hydrogen or taken together with R 2 forms an oxo
  • R 4 is hydrogen, together with R 4a forms an oxo, oxirane or methylene, or together with R 5a and the carbon atoms to which they are attached form an oxetane ring;
  • R 4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, -OCOR 30 , or together with R 4 forms an oxo, oxirane or methylene;
  • R 5 is hydrogen or together with R 5a forms an oxo
  • R 5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R 5 forms an oxo, or together with R 4 and the carbon atoms to which they are attached form an oxetane ring;
  • R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R 6a forms an oxo;
  • R 6a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R 6 forms an oxo;
  • R 7 is hydrogen or together with R 7a forms an oxo
  • R 7a is hydrogen, halogen, protected hydroxy
  • R 9 is hydrogen or together with R 9a forms an oxo
  • R 9a is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R 9 forms an oxo;
  • R 10 is hydrogen or together with R 10a forms an oxo
  • R 10a is hydrogen, -OCOR 29 , hydroxy, or protected hydroxy, or together with R 10 forms an oxo
  • R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R 1 forms a carbonate;
  • R 14a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl
  • R 28 is hydrogen, acyl, hydroxy protecting group or a functional group which increases the solubility of the taxane derivative
  • R 29 , R 30 , and R 31 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl.
  • DMAP means p-dimethylamino pyridine
  • DMF dimethylformamide
  • LDA lithium diisopropylamide
  • LHMDS lithium
  • LAH lithium aluminum hydride
  • Red-Al sodium bis (2-methoxyethoxy) aluminum hydride
  • AIBN azo-(bis)- isobutyronitrile
  • 10-DAB 10-desacetylbaccatin III
  • FAR means 2-chloro-1,1,2-trifluorotriethylamine
  • protected hydroxy means -OR wherein R is a hydroxy protecting group; sulfhydryl protecting group” includes, but is not limited to, hemithioacetals such as
  • amine protecting group includes, but is not limited to, carbamates, for example,
  • hydroxy protecting group includes, but is not limited to, ethers such as methyl, t-butyl, benzyl,
  • esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and
  • alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl
  • cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl
  • phenyl or benzyl carbonates optionally substituted on the ring with one or more C 1-6 alkoxy, or nitro.
  • Other hydroxyl, sulfhydryl and amine protecting groups may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981.
  • alkyl groups described herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight, branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • alkenyl groups described herein are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
  • alkynyl groups described herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
  • aryl moieties described herein either alone or with various substituents, contain from 6 to 15 carbon atoms and include phenyl.
  • Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl.
  • heteroaryl moieties described herein either alone or with various substituents, contain from 5 to 15 atoms and include, furyl, thienyl, pyridyl and the like.
  • Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, and amido.
  • acyloxy groups described herein contain alkyl, alkenyl, alkynyl, aryl or heteroaryl groups.
  • moieties described herein may be alkyl, alkenyl,
  • alkynyl, aryl, heteroaryl and/or may contain nitrogen, oxygen, sulfur, halogens and include, for example, lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chloro or fluoro, nitro, amino, and keto.
  • the substituents of the cyclic nucleus of the taxane correspond to the substituents present on baccatin III or 10-DAB. That is, R 14 and R 14a are hydrogen, R 10 is hydrogen, R 10a is hydroxy or acetoxy, R 9 and R 9a together form an oxo, R 7 is hydrogen, R 7a is hydroxy, R 5 is hydrogen, R 5a and R 4 and the carbons to which they are attached form an oxetane ring, R 4a is acetoxy, R 2 is hydrogen, R 2a is benzoyloxy, and R 1 is hydroxy.
  • the taxane has a
  • R 14 may be hydroxy
  • R 2 may be hydroxy or -OCOR 31 wherein R 31 is hydrogen, alkyl or selected from the group comprising
  • Z is alkyl, hydroxy, alkoxy, halogen, or
  • R 9a may be hydrogen and R 9 may be hydrogen or hydroxy
  • R 7a may be hydrogen and R 7 may be acetoxy or other acyloxy or halogen
  • R 10 and R 10a may each be hydrogen or together form an oxo.
  • X 1 is -OH
  • X 2 is hydrogen
  • X 3 is alkyl
  • X 4 is hydrogen
  • X 5 is -COX 10 or -COOX 10
  • X 10 is alkyl, alkenyl, alkynyl, aryl, furyl, thienyl or other heteroaryl and the taxane has the 2'R, 3'S configuration.
  • X 3 is isopropyl, cyclopropyl, n-butyl, t-butyl, cyclobutyl, cyclohexyl or the substituted analogs thereof
  • X 5 is -COX 10 or -COOX 10 and X 10 is furyl, thienyl, pyridyl, alkyl substituted furyl or thienyl, tert-, iso- or n-butyl, ethyl, iso- or n-propyl, cyclopropyl, cyclohexyl, allyl, crotyl, 1,3- diethoxy-2-propyl, 2-methoxyethyl, amyl, neopentyl,
  • Taxanes having the general formula 3 may be obtained by reacting a ⁇ -lactam with alkoxides having the taxane tricyclic or tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a ⁇ -amido ester substituent at C-13.
  • the ⁇ -lactams have the following structural formula:
  • ⁇ -acetoxy acetyl chloride is prepared from glycolic acid, and, in the presence of a tertiary amine, it cyclocondenses with imines prepared from aldehydes and p-methoxyaniline to give 1-p-methoxyphenyl-3-acyloxy-4- arylazetidin-2-ones.
  • the p-methoxyphenyl group can be readily removed through oxidation with eerie ammonium nitrate, and the acyloxy group can be hydrolyzed under standard conditions familiar to those experienced in the art to provide 3-hydroxy-4-arylazetidin-2-ones.
  • X 1 is preferably -OX 6 and X 6 is a hydroxy protecting group.
  • Protecting groups such as 2-methoxypropyl (“MOP”), 1-ethoxyethyl (“EE”) are examples of protecting groups.
  • racemic ⁇ -lactams may be resolved into the pure enantiomers prior to protection by recrystallization of the corresponding 2-methoxy-2-(trifluoromethyl) phenylacetic esters.
  • reaction described hereinbelow in which the ⁇ -amido ester side chain is attached has the advantage of being highly
  • alkoxides having the tricyclic or tetracyclic taxane nucleus and a C-13 metallic oxide or ammonium oxide substituent have the following structural formula:
  • R 1 - R 14a are as previously defined and M
  • the alkoxide has the tetracyclic taxane nucleus and corresponds to the structural formula:
  • the alkoxides can be prepared by reacting an alcohol having the taxane nucleus and a C-13 hydroxyl group with an organometallic compound in a suitable solvent.
  • the alcohol is a protected baccatin III, in particular, 7-O-triethylsilyl baccatin
  • reaction product may then optionally be acetylated with 5 equivalents of CH 3 COCl and 25 mL of pyridine/mmol of 4a at 0 °C under an argon atmosphere for 48 hours to provide 86% yield of 7-O-triethylsilyl baccatin III (4b).
  • the 7-protected baccatin III (4b) is reacted with an organometallic compound such as LHMDS in a solvent such as tetrahydrofuran (THF), to form the metal alkoxide 13-O-lithium-7-O-triethylsilyl baccatin III as shown in the following reaction scheme:
  • 13-O-lithium-7-O-triethylsilyl baccatin III reacts with a ⁇ -lactam in which X 1 is preferably -OX 6 , (X 6 being a hydroxy protecting group) and X 2 - X 5 are as previously defined to provide an intermediate in which the C-7 and C-2' hydroxyl groups are protected.
  • the protecting groups are then hydrolyzed under mild conditions so as not to disturb the ester linkage or the taxane
  • Both the conversion of the alcohol to the alkoxide and the ultimate synthesis of the taxane derivative can take place in the same reaction vessel.
  • the ⁇ -lactam is added to the reaction vessel after formation therein of the alkoxide.
  • Antitumor compositions herein may be made up in any suitable form appropriate for desired use; e.g., oral, parenteral or topical administration.
  • parenteral administration are intramuscular, intravenous, intraperitoneal, rectal and subcutaneous administration.
  • the diluent or carrier ingredients should not be such as to diminish the therapeutic effects of the antitumor compounds.
  • Suitable dosage forms for oral use include tablets, dispersible powders, granules, capsules,
  • Inert diluents and carriers for tablets include, for example, calcium carbonate, sodium carbonate, lactose and talc. Tablets may also contain granulating and disintegrating agents such as starch and alginic acid, binding agents such as starch, gelatin and acacia, and lubricating agents such as magnesium stearate, stearic acid and talc. Tablets may be uncoated or may be coated by unknown techniques; e.g., to delay disintegration and absorption. Inert diluents and carriers which may be used in capsules include, for example, calcium carbonate, calcium
  • Suspensions, syrups and elixirs may contain conventional excipients, for example, methyl cellulose, tragacanth, sodium alginate; wetting agents, such as lecithin and polyoxyethylene stearate; and preservatives, e.g., ethyl- p-hydroxybenzoate.
  • Dosage forms suitable for parenteral administration include solutions, suspensions,
  • dispersions emulsions and the like. They may also be manufactured in the form of sterile solid compositions which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain
  • (3) may be improved by modification of the C2' and/or C7 substituents. For instance, water solubility may be increased if X 1 is -OX 6 and R 7a is -OR 28 , and X 6 and R 28 are independently hydrogen or -COGCOR 1 wherein
  • R 3 (CH 2 ) n NR 6 R 7 ; (CH 2 ) n N ⁇ R 6 R 7 R 8 X ⁇
  • n 1 to 3
  • R 4 hydrogen, lower alkyl containing 1 to 4 carbons
  • R 5 hydrogen, lower alkyl containing 1 to 4 carbons, benzyl, hydroxyethyl, CH 2 CO 2 H, dimethylaminoethyl
  • R 6 R 7 lower alkyl containing 1 or 2 carbons, benzyl or R 6 and
  • R 8 lower alkyl containing 1 or 2 carbons, benzyl
  • solubility may be increased when
  • Patent No. 5,059,699 (incorporated herein by reference).
  • Taxanes having alternative C9 keto substituent may be prepared by selectively reduced to yield the corresponding C9 ⁇ -hydroxy derivative.
  • the reducing agent is preferably a borohydride and, most preferably, tetrabutylammoniumboro-hydride (Bu 4 NBH 4 ) or
  • the C13 hydroxy group of 7- protected-9 ⁇ -hydroxy derivative 6 may be protected with trimethylsilyl or other protecting group which can be selectively removed relative to the C7 hydroxy protecting group as illustrated in Reaction Scheme 2, to enable further selective manipulation of the various
  • 10-oxo derivative 11 can be provided by oxidation of 10- desacetyl derivative 8. Thereafter, the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9- acetoxy-10-oxo-taxol or other 9-acetoxy-10-oxotetracylic taxanes having a C13 side chain.
  • the C9 acetate group can be selectively removed by reduction of 10-oxo derivative 11 with a reducing agent such as samarium diiodide to yield 9-desoxo-10-oxo derivative 12 from which the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9-desoxo-10-oxo-taxol or other 9-desoxo-10-oxotetracylic taxanes having a C13 side chain.
  • a reducing agent such as samarium diiodide
  • Reaction Scheme 4 illustrates a reaction in which 10-DAB is reduced to yield pentaol 13.
  • the C7 and C10 hydroxyl groups of pentaol 13 can then be selectively protected with the triethylsilyl or another protecting group to produce triol 14 to which a C13 side chain can
  • Taxanes having C9 and/or C10 acyloxy substituents other than acetate can be prepared using 10- DAB as a starting material as illustrated in Reaction Scheme 5.
  • Reaction of 10-DAB with triethylsilyl chloride in pyridine yields 7-protected 10-DAB 15.
  • the C10 hydroxy substituent of 7-protected 10-DAB 15 may then be readily acylated with any standard acylating agent to yield derivative 16 having a new C10 acyloxy substituent.
  • derivative 16 yields 9 ⁇ -hydroxy derivative 17 to which a C13 side chain may be attached.
  • the C10 and C9 groups can be caused to migrate as set forth in Reaction Scheme 2, above.
  • Taxanes having alternative C2 and/or C4 esters can be prepared using baccatin III and 10-DAB as starting materials.
  • the C2 and/or C4 esters of baccatin III and 10-DAB can be selectively reduced to the corresponding alcohol (s) using reducing agents such as LAH or Red-Al, and new esters can thereafter be substituted using standard acylating agents such as anhydrides and acid chlorides in combination with an amine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine.
  • the C2 and/or C4 alcohols may be converted to new C2 and/or C4 esters through formation of the corresponding alkoxide by treatment of the alcohol with a suitable base such as LDA followed by an acylating agent such as an acid chloride.
  • a suitable base such as LDA
  • an acylating agent such as an acid chloride.
  • derivatives or analogs may be produced using the same series of reactions (except for the protection of the C10 hydroxy group) by simply replacing 10-DAB with baccatin III as the starting material.
  • 9-desoxo derivatives of the baccatin III and 10-DAB analogs having different substituents at C2 and/or C4 can then be prepared by reducing the C9 keto substituent of these analogs and carrying out the other reactions described above.
  • triol 18 Deprotonation of triol 18 with LDA followed by introduction of an acid chloride selectively gives the C4 ester.
  • an acid chloride for example, when acetyl chloride was used, triol 18 was converted to 1,2 diol 4 as set forth in Reaction Scheme 7.
  • Triol 18 can also readily be converted to the 1,2 carbonate 19.
  • Acetylation of carbonate 19 under vigorous standard conditions provides carbonate 21 as described in Reaction Scheme 8; addition of alkyllithiums or Grignard reagents to carbonate 19 provides the C2 ester having a free hydroxyl group at C4 as set forth in Reaction Scheme 6
  • other C4 substituents can be provided by reacting carbonate 19 with an acid chloride and a tertiary amine to yield carbonate 22 which is then reacted with alkyllithiums or
  • baccatin III may be used as a starting material and reacted as shown in Reaction Scheme 10. After being protected at C7 and C13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 24. Tetraol 24 is converted to carbonate 25 using Cl 2 CO and pyridine, and carbonate 25 is acylated at C10 with an acid chloride and pyridine to produce carbonate 26 (as shown) or with acetic anhydride and pyridine (not shown). Acetylation of carbonate 26 under vigorous standard conditions provides carbonate 27 which is then reacted with alkyl lithiums to provide the baccatin III derivatives having new substituents at C2 and C10.
  • 10-desacetoxy derivatives of baccatin III and 10-desoxy derivatives of 10-DAB may be prepared by reacting baccatin III or 10-DAB (or their derivatives) with samarium diiodide. Reaction between the tetracyclic taxane having a C10 leaving group and samarium diiodide may be carried out at 0°C in a solvent such as
  • the samarium diiodide selectively abstracts the C10 leaving group; C13 side chains and other substituents on the tetracyclic nucleus remain undisturbed. Thereafter, the C9 keto substituent may be reduced to provide the corresponding 9-desoxo-9 ⁇ - hydroxy-10-desacetyoxy or 10-desoxy derivatives as otherwise described herein.
  • C7 dihydro and other C7 substituted taxanes can be prepared as set forth in Reaction Schemes 11, 12 and 12a.
  • Baccatin III may be converted into 7-fluoro baccatin III by treatment with FAR at room temperature in THF solution.
  • Other baccatin derivatives with a free C7 hydroxyl group behave similarly.
  • 7-chloro baccatin III can be prepared by treatment of baccatin III with methane sulfonyl chloride and triethylamine in methylene chloride solution containing an excess of triethylamine
  • Taxanes having C7 acyloxy substituents can be prepared as set forth in Reaction Scheme 12a, 7,13- protected 10-oxo-derivative 11 is converted to its corresponding C13 alkoxide by selectively removing the C13 protecting group and replacing it with a metal such as lithium. The alkoxide is then reacted with a ⁇ -lactam or other side chain precursor. Subsequent hydrolysis of the C7 protecting groups causes a migration of the C7 hydroxy substituent to C10, migration of the C10 oxo substituent to C9, and migration of the C9 acyloxy substituent to C7.
  • this hydroxylated taxane having the various C2, C4, etc. functional groups described above may also be prepared by using this hydroxylated taxane.
  • the C14 hydroxy group together with the C1 hydroxy group of 10-DAB can be converted to a 1,2- carbonate as described in C&EN or it may be converted to a variety of esters or other functional groups as
  • the solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added.
  • the mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane.
  • the solution was warmed to 0 °C and kept at that temperature for 1 h before 1.0 mL of a 10% solution of AcOH in THF was added.
  • the mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane.
  • H6 ⁇ 2.44(s, 3H, 4Ac), 2.31 (m, 2H, H14), 2.24 (s, 3H, 10Ac), 1.87 (s, 3H, Mel8) 1.83 (m, 1H, H6 ⁇ ), 1.9-0.9 (m, 21H, cyclohexyl), 1.67 (s, 3H, Me19), 1.2 (s, 3H, Me17), 1.14 (s, 3H, Me16).

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Abstract

Dérivés de taxane à chaîne latérale C13 à substitution alkyle.
PCT/US1993/010816 1992-11-13 1993-11-01 Taxanes a chaine laterale a substitution alkyle et compositions pharmaceutiques les contenant WO1994010997A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP94901360A EP0667772B9 (fr) 1992-11-13 1993-11-01 Taxanes a chaine laterale a substitution alkyle et compositions pharmaceutiques les contenant
AT94901360T ATE240099T1 (de) 1992-11-13 1993-11-01 Taxane, die eine alkyl-substituierte seitenkette haben, und diese enthaltende pharmazeutische zusammensetzungen
DK94901360T DK0667772T3 (da) 1992-11-13 1993-11-01 Texaner med en alkylsubstitueret sidekæde og farmaceutiske præparater indeholdende disse
CA002147854A CA2147854C (fr) 1992-11-13 1993-11-01 Taxanes possedant une chaine laterale avec substitution alkylique; compositions pharmaceutiques qui en renferment
DE69332979T DE69332979T2 (de) 1992-11-13 1993-11-01 Taxane, die eine alkyl-substituierte seitenkette haben, und diese enthaltende pharmazeutische zusammensetzungen
ES94901360T ES2199955T3 (es) 1992-11-13 1993-11-01 Taxanos que tienen una cadena lateral alquilo sustituido y composiciones farmaceuticas que las contienen.
JP51229994A JP3933196B2 (ja) 1992-11-13 1993-11-01 アルキル置換側鎖を有するタキサンおよびそれを含有する薬剤組成物
AU55976/94A AU689451B2 (en) 1992-11-13 1993-11-01 Taxanes having an alkyl substituted side-chain and pharmaceutical compositions containing them

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US07/976,331 1992-11-13
US07/976,331 US5284865A (en) 1991-09-23 1992-11-13 Cyclohexyl substituted taxanes and pharmaceutical compositions containing them
US08/005,229 1993-01-15
US08/005,229 US5338872A (en) 1993-01-15 1993-01-15 Process for the preparation of 10-desacetoxybaccatin III and 10-desacetoxytaxol and derivatives thereof
US08/010,798 US5399726A (en) 1993-01-29 1993-01-29 Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups
US08/010,798 1993-01-29
US08/026,978 US5990325A (en) 1993-03-05 1993-03-05 Process for the preparation of 9-desoxotaxol, 9-desoxobaccatin III and analogs thereof
US08/026,978 1993-03-05
US08/034,247 US5430160A (en) 1991-09-23 1993-03-22 Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides
US08/034,247 1993-03-22
US9475693A 1993-07-20 1993-07-20
US08/094,756 1993-07-20

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JP (1) JP3933196B2 (fr)
CN (2) CN1075066C (fr)
AT (2) ATE240099T1 (fr)
AU (1) AU689451B2 (fr)
DE (2) DE69332979T2 (fr)
DK (2) DK0667772T3 (fr)
ES (2) ES2199955T3 (fr)
HK (1) HK1032960A1 (fr)
IL (1) IL107555A (fr)
PT (2) PT667772E (fr)
WO (1) WO1994010997A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013495A1 (fr) * 1994-10-28 1996-05-09 The Research Foundation Of State University Of New York Derives taxoides, leur preparation et leur utilisation en tant qu'agents antitumoraux
EP0712854A1 (fr) * 1994-11-17 1996-05-22 Tanabe Seiyaku Co., Ltd. Dérivés du baccatin et procédés pour le préparer
US5677470A (en) * 1994-06-28 1997-10-14 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
EP0856512A2 (fr) * 1997-01-24 1998-08-05 Virginia Tech Intellectual Properties, Inc. 1-Déoxy-paclitaxels, méthode de préparation et utilisation pharmaceutique
EP0927175A1 (fr) * 1996-05-06 1999-07-07 Florida State University 1-deoxy baccatine iii, 1-deoxy taxol, analogues de 1-deoxy taxol, et procedes de fabrication correspondants
US6458976B1 (en) 1994-10-28 2002-10-01 The Research Foundation Of State University Of New York Taxoid anti-tumor agents, pharmaceutical compositions, and treatment methods
US6500858B2 (en) 1994-10-28 2002-12-31 The Research Foundation Of The State University Of New York Taxoid anti-tumor agents and pharmaceutical compositions thereof
WO2010079499A3 (fr) * 2008-02-21 2011-09-09 Sun Pharma Advanced Research Company Ltd., Nouvel hydrazide contenant des conjugués de taxane

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1393438B (zh) * 2001-06-21 2010-11-03 中国医学科学院药物研究所 紫杉烷衍生物及其制法和用途
CN100390255C (zh) * 2006-03-03 2008-05-28 清华大学 一种污泥燃料棒及其制备方法
WO2008117775A1 (fr) * 2007-03-27 2008-10-02 Daiichi Sankyo Company, Limited Taxanes ayant une structure de cycle oxétane
WO2017223093A2 (fr) * 2016-06-20 2017-12-28 Yeti Coolers, Llc Couvercle pour récipient

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4942184A (en) * 1988-03-07 1990-07-17 The United States Of America As Represented By The Department Of Health And Human Services Water soluble, antineoplastic derivatives of taxol
US5175315A (en) * 1989-05-31 1992-12-29 Florida State University Method for preparation of taxol using β-lactam

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4960790A (en) * 1989-03-09 1990-10-02 University Of Kansas Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof
EP0582469A2 (fr) * 1992-08-06 1994-02-09 Wisconsin Alumni Research Foundation Procédé de préparation de composés du type taxol à partir de précurseurs bèta-lactames
CA2111527C (fr) * 1992-12-24 2000-07-18 Jerzy Golik Phosphonooxymethylethers de derives du taxane

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4942184A (en) * 1988-03-07 1990-07-17 The United States Of America As Represented By The Department Of Health And Human Services Water soluble, antineoplastic derivatives of taxol
US5175315A (en) * 1989-05-31 1992-12-29 Florida State University Method for preparation of taxol using β-lactam

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5677470A (en) * 1994-06-28 1997-10-14 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
WO1996013495A1 (fr) * 1994-10-28 1996-05-09 The Research Foundation Of State University Of New York Derives taxoides, leur preparation et leur utilisation en tant qu'agents antitumoraux
US6835746B2 (en) 1994-10-28 2004-12-28 The Research Foundation Of State University Of New York Taxoid anti-tumor agents and pharmaceutical compositions thereof
US6500858B2 (en) 1994-10-28 2002-12-31 The Research Foundation Of The State University Of New York Taxoid anti-tumor agents and pharmaceutical compositions thereof
US6458976B1 (en) 1994-10-28 2002-10-01 The Research Foundation Of State University Of New York Taxoid anti-tumor agents, pharmaceutical compositions, and treatment methods
US6096909A (en) * 1994-10-28 2000-08-01 The Research Foundation Of State University Of New York Taxoid anti-tumor agents and pharmaceutical compositions thereof
EP0712854A1 (fr) * 1994-11-17 1996-05-22 Tanabe Seiyaku Co., Ltd. Dérivés du baccatin et procédés pour le préparer
US5589502A (en) * 1994-11-17 1996-12-31 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
US5608073A (en) * 1994-11-17 1997-03-04 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
EP0927175A4 (fr) * 1996-05-06 2002-05-22 Univ Florida State 1-deoxy baccatine iii, 1-deoxy taxol, analogues de 1-deoxy taxol, et procedes de fabrication correspondants
EP0927175A1 (fr) * 1996-05-06 1999-07-07 Florida State University 1-deoxy baccatine iii, 1-deoxy taxol, analogues de 1-deoxy taxol, et procedes de fabrication correspondants
EP0856512A3 (fr) * 1997-01-24 1998-12-09 Virginia Tech Intellectual Properties, Inc. 1-Déoxy-paclitaxels, méthode de préparation et utilisation pharmaceutique
EP0856512A2 (fr) * 1997-01-24 1998-08-05 Virginia Tech Intellectual Properties, Inc. 1-Déoxy-paclitaxels, méthode de préparation et utilisation pharmaceutique
WO2010079499A3 (fr) * 2008-02-21 2011-09-09 Sun Pharma Advanced Research Company Ltd., Nouvel hydrazide contenant des conjugués de taxane

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JPH08503219A (ja) 1996-04-09
IL107555A0 (en) 1994-02-27
AU689451B2 (en) 1998-04-02
DE69333989T2 (de) 2006-08-17
EP0667772A4 (fr) 1995-12-20
IL107555A (en) 2006-08-01
DE69333989D1 (de) 2006-05-04
DE69332979D1 (de) 2003-06-18
HK1032960A1 (en) 2001-08-10
EP0667772B9 (fr) 2004-08-04
DK0667772T3 (da) 2003-09-01
DE69332979T2 (de) 2004-01-08
CN1075066C (zh) 2001-11-21
EP0667772B1 (fr) 2003-05-14
DK1146043T3 (da) 2006-07-03
EP0667772A1 (fr) 1995-08-23
PT1146043E (pt) 2006-06-30
ES2199955T3 (es) 2004-03-01
PT667772E (pt) 2003-09-30
ES2259303T3 (es) 2006-10-01
CN100341853C (zh) 2007-10-10
EP1146043A1 (fr) 2001-10-17
CN1285351A (zh) 2001-02-28
EP1146043B1 (fr) 2006-03-08
CN1092417A (zh) 1994-09-21
JP3933196B2 (ja) 2007-06-20
ATE319698T1 (de) 2006-03-15
ATE240099T1 (de) 2003-05-15
AU5597694A (en) 1994-06-08

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